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Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras-Raf-MAPK signalling |
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| Authors: | Yongye Huang Kexun Yuan Meifang Tang Jiaming Yue Lijun Bao Shuang Wu Yanxin Zhang Yin Li Yihang Wang Xu Ou Jiaxin Gou Qi Zhao Lin Yuan |
| Institution: | 1. College of Life and Health Sciences, Northeastern University, Shenyang, China
Contribution: Conceptualization (equal), Funding acquisition (equal), Project administration (equal), Writing - original draft (equal), Writing - review & editing (equal);2. College of Life and Health Sciences, Northeastern University, Shenyang, China Contribution: ?Investigation (equal);3. National Academy of Innovation Strategy, Beijing, China Contribution: Writing - review & editing (equal);4. School of Computer Science and Software Engineering, University of Science and Technology Liaoning, Anshan, China;5. Institute of Health Science, China Medical University, Shenyang, China |
| Abstract: | Melatonin exhibits antitumour activities in the treatment of many human cancers. In the present study, we aimed to improve the therapeutic potential of melatonin in gastric cancer. Our results confirmed that melatonin dose-dependently suppressed the proliferation and necrosis, and increased G0/G1 phase arrest, apoptosis, autophagy and endoplasmic reticulum (ER) stress. The Ras-Raf-MAPK signalling pathway was activated in cells after melatonin treatment. RNA-seq was performed and GSEA analysis further confirmed that many down-regulated genes in melatonin-treated cells were associated with proliferation. However, GSEA analysis also indicated that many pathways related to metastasis were increased after melatonin treatment. Subsequently, combinatorial treatment was conducted to further investigate the therapeutic outcomes of melatonin. A combination of melatonin and thapsigargin increased the apoptotic rate and G0/G1 cell cycle arrest when compared to treatment with melatonin alone. Melatonin in combination with thapsigargin triggered the increased expression of Bip, LC3-II, phospho-Erk1/2 and phospho-p38 MAPK. In addition, STF-083010, an IRE1a inhibitor, further exacerbated the decrease in survival rate induced by combinatorial treatment with melatonin and thapsigargin. Collectively, melatonin was effective in gastric cancer treatment by modifying ER stress. |
| Keywords: | autophagy combinatorial treatment ER stress melatonin RNA-seq |